ABSTRACT Hereditary inclusion body myopathy (h-IBM), Paget disease of bone (PDB) and/or frontotemporal dementia (FTD), also called IBMPFD was recognized as a distinct clinical syndrome in 2000 by Kimonis et al. who identified that the disease is caused by mutations in the Valosin Containing Protein (VCP) gene. Over 30 families from North and South America, Europe and Australia harboring 15 unique VCP missense mutations have been recruited for our gene discovery studies. We now propose to perform detailed clinical studies in 50 affected and 25 unaffected individuals to determine the rate of progression of the disease so that the effects of future treatment strategies can be objectively evaluated. We have created a knock-in mouse model that demonstrates decreased muscle strength, disrupted muscle fibers, TDP-43 and ubiquitin positive inclusion bodies and vacuoles in muscle, cognitive deficits and Paget-like bone lesions. Additionally, we have identified a number of molecular and cellular defects in patients'muscle cells and tissues. The aims of the proposed project are: 1. Clinical studies in patients with myopathy associated with Paget disease of the bone (IBMPFD) to evaluate disease progression 2. To characterize the phenotype and tissue pathology of the R155H knock-in mouse model of IBMPFD 3. To characterize the molecular pathogenesis of muscle from patients and mice at different stages of the myopathy 4. To clarify the cellular pathology of mutant primary myoblasts from patients Insight into the disease pathogenesis gained by our detailed clinical evaluations, analysis of muscle tissue from patients and mice and patient myoblasts will provide hypotheses that can be tested by parallel studies of patients and knock-in VCP mice.